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 Table of Contents  
REVIEW ARTICLE
Year : 2019  |  Volume : 2  |  Issue : 1  |  Page : 81-91

Cell-based treatment strategies for intervertebral disc degeneration: An overview on potentials and shortcomings


Sunshine Medical Academy for Research and Training, Sunshine Hospitals, Secunderabad, Telangana, India

Date of Web Publication11-Jan-2019

Correspondence Address:
Dr. G P V Subbaiah
Sunshine Medical Academy for Research and Training, Sunshine Hospitals, Secunderabad - 500 003, Telangana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/isj.isj_21_17

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  Abstract 


The intervertebral discs (IVDs) are the cushioning pads of fibrocartilage, which are immeasurably vital for the uprightness of vertebral column and for its function. IVD provides flexibility, tensile strength to the spine, and also cope up with varied types of biomechanical stresses. IVD degeneration (IVDD) is one of the musculoskeletal disorders mostly seen in older population, and it is the foremost cause of low back pain and consequences of IVDD are disc herniation, spinal stenosis, and degenerative lumbar scoliosis. Yet the therapeutic options are restricted and the treatments given remain unsatisfactory putting more economical burden on world's population. IVDD is considered as a multifactorial disorder, due to the involvement of factors such as genetic inheritance, alterations in cellular composition, and anabolic and catabolic reactions, which could initiate degenerative process in the IVD. However, our conception on IVD genesis and the etiopathology of IVDD have given us an opportunity for exploring and formulate appropriate therapies to tackle IVDD. The cell therapy gives scope for sustained matrix synthesis, controlled inflammation, and prevention of osteophyte formation in IVD. The present review focuses on the existing issues related to current therapeutic approaches and about latest evidence on cell therapy-based regeneration of IVD and maintaining the microenvironment of cellular matrix which holds a promise for future therapeutic applications.

Keywords: Cell therapy, cellular matrix, intervertebral disc degeneration, nucleus pulposus, stem cells


How to cite this article:
Sampara P, Banala RR, Vemurit SK, Gurava Reddy A V, Subbaiah G P. Cell-based treatment strategies for intervertebral disc degeneration: An overview on potentials and shortcomings. Indian Spine J 2019;2:81-91

How to cite this URL:
Sampara P, Banala RR, Vemurit SK, Gurava Reddy A V, Subbaiah G P. Cell-based treatment strategies for intervertebral disc degeneration: An overview on potentials and shortcomings. Indian Spine J [serial online] 2019 [cited 2019 Jan 15];2:81-91. Available from: http://www.isjonline.com/text.asp?2019/2/1/81/249894

Prasanthi Sampara, Rajkiran Reddy Banala, Satish Kumar Vemurit: Indicates equal authorship





  Introduction Top


Intervertebral disc degeneration (IVDD) is a multifaceted chronic process with cell-mediated response toward alterations in the cellular microenvironment within the disc causing progressive loss of proteoglycans and water content in the nucleus pulposus (NP) and annulus fibrosus (AF), thereby causing progressive structural failure. IVDD is a major cause of low back pain and as such is a significant health problem. A study done by Pellisé et al. estimated that 84% of the world population experiences low back pain at some point in their lifetime.[1] According to a study published in Lancet (2012), on Global Burden of Disease, it is estimated that 632 million people worldwide are affected by low back pain.[2]

The IVD is a complex fibrocartilaginous structure that provides mechanical support and flexibility to the vertebral column.[3] The IVD is made up of three distinct components; the NP is the central gelatinous layer and it consists of proteoglycans, predominantly aggrecan and collagen Type II. The second component AF is highly organized and consists of collagen Type I fibers. The third component is the cartilaginous endplates (CEPs) consisting of hyaline cartilage that facilitates the diffusion of nutrients and oxygen to the avascular internal structure of IVD.[4] [Figure 1] illustrates characteristics of a healthy disc and a degenerated disc. The healthy discs maintain a balance between anabolic and catabolic processes, whereas the imbalance between the synthesis and catabolism of the extracellular matrix (ECM) components may contribute to the IVDD.[5] This imbalance between the catabolic and anabolic processes results in the loss of proteoglycans and water content in the NP and finally contributes to the degeneration of the IVD.[6] When a healthy IVD is compared to the degenerated IVD, it is observed that the degenerated IVD has inflated inflammation, innervation and angiogenesis, the boundary between the NP and AF is damaged, and the extension of the interlamellar space comprises of collagen bundles surrounded by the AF that usually cause disc bulging. The effects of the degenerative cascade are inflammation, cartilage endplate-calcified osteophyte formation in the adjacent vertebral bone, derangement and delamination of AF, and in-growth of pain nerves and blood vessels into a typically aneural and avascular tissue.[7] Hence, the reinforcement of cells from the surrounding environment to augment the supply of viable and functioning cells is an aspect of regenerative process of an organ.
Figure 1: A comparative profile of the healthy and degenerative disc. Various morphological changes and structural changes such as disc bulging, blood vessel in growth, cartilaginous endplate calcification, and loss of the boundaries can be observed in the degenerative intervertebral disc when compared to the healthy disc

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The IVDD is thought to initiate in the NP where there is loss of normal matrix and increased matrix metalloproteinase (MMP) production which is responsible for the catabolic activity.[8] As the degeneration of IVD advances within the NP cells, the collagen Type II is progressively substituted by more fibrous collagen Type I, and therefore, the overall proteoglycan composition of the NP is abridged and changed by decreased synthesis of aggrecan, thereby leading to decreased hydration of the ECM within the NP. At the same time, the matrix degradation is stimulated by the upregulation of MMPs and a disintegrin and metalloproteinase with thrombospondin motifs. The structural changes within the ECM throughout the degeneration of IVD are also associated with the cellular changes such as increased cell apoptosis and cell senescence. The activation of apoptotic pathways and cell senescence is believed to be having major impact in IVDD [Figure 2].[9]
Figure 2: The changes are involved in the intervertebral disc degeneration: The changes include structural changes, cellular changes, genetic variations, and the dysregulation of inflammatory mediators and cytokines

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The current treatment modalities for IVDD include pain medications, physical therapy, epidural steroid injections, nucleotomy, spinal fusion, and disc replacement. The efficacy and long-term outcomes of these surgical and nonsurgical treatments are neither predictable nor reliable as they mainly focus on symptomatic relief with no clinical therapy targeting the reversal of disc degeneration.[10] Recent progress in tissue engineering and regenerative medicine has increased the interest in developing a biological approach to this condition through which cells alone or together with biomaterials would be implanted into the NP to both repopulate and stimulate native cells to produce a healthier ECM. In this article, we review the current understanding of the pathogenesis of IVDD and discuss the cell-based treatment strategies based on the cellular and molecular features of the IVD. The cell therapy can be done using biomaterials and cells either individually or in combination for the regeneration of IVD.

Cell therapy designates the most recent phase of revolution in the field of regenerative medicine and biotechnology. Cell therapies offer an assurance of treating and changing the diseases that cannot be addressed efficiently by the predominant treatments. The main objective of cell therapy is to repair the mechanisms underlying disease initiation and progression and achieved through trophic effect or by cell replacement. Cell therapy uses various cell types, such as stem cells, progenitor cells, or primary cells that can be either directly transplanted into the affected region or recruited from the patient's own tissues to stimulate self-repair. There are two major mechanisms of action that are involved in cell therapies. One is based on the replacement of injured cells or tissue by engraftment into the damaged tissue and the second mechanism is based on the stimulation of endogenous tissue self-healing processes through trophic effects mediated by cytokine and growth factor secretion.[11] Currently, cell therapies are being used in the treatment of many neurologic, cardiac, and orthopedic diseases. Research is still being done on the use of cell therapies in IVD. Cell therapies for IVD regeneration currently depend on the transplantation of IVD cells or stem cells directly into the affected site on the degenerated disc.


  Materials and Methods Top


We conducted an electronic search for research articles published only in English in the area of IVDD and cell therapies strategies using particular keywords such as IVDD and cell therapies, tissue engineering and intervertebral disc, regeneration of disc, and stem cells or progenitors. We have limited ourselves from considering published materials which were older than 20 years. During our search, we have come across various types of articles including original research, reviews, and also clinical trial information from databases of NHS evidence, TRIP, Cochrane systemic, PubMed, etc. Our focus was mainly on the employment of stem cells and disc cells such as NP, AF, and chondrocytes taken from autologous and heterologous source in treatment and regeneration of disc with limited side effects or with chances of sustaining for long time.

Cell therapy

Cell-based therapy is the optimal treatment strategy in mid-stage degeneration because it directly addresses the decreased number of viable chondrocytes and disc cells within the diseased disc space. In the past decade, cellular therapy has gained significant attention for addressing the regeneration of the disc by controlling cell loss and proteoglycans components.[12] Cell-based therapy can be performed using different types of differentiated cells, such as NP cells, AF cells, cartilaginous chondrocytes, and progenitor cells.[13] The choice of the cells depends on certain practical issues such as accessibility, abundance, and safety concerns that include tumorigenesis and immunogenicity.[10] The avascular nature of the IVD creates an acidic, hypertonic, hypoglycemic, and hypoxic microenvironment forming a barrier for exogenous cells to survive.[14] Therefore, in cell-based therapy, choosing a cell source is essential for the successful outcome of the regeneration of the IVD as the implanted cells need to be able to survive and produce tissue of the desired quantity.[15] The abundant animal studies conducted till date include the use of stem cells and IVD cells which are taken from autologous, allogeneic, and xenogeneic sources. Autologous cells are considered to be ideal as they can overcome the concerns over disease transmission and immune responses and these cells harvested from bone marrow and adipose tissue can be used for therapy. Allogeneic cells are ideal as they have higher expansion potential than most autologous cells and could be isolated from umbilical cord blood, umbilical tissue, or articular surface. Xenogeneic cells have only been tested in animal models; most of these studies used various human cells to repair injured animal IVDs.[16]

Autologous disc cell and articular chondrocytes transplantation

Tissue-specific cells are in principle the ideal cell types for cell-based therapy and were first to be studied. The implantation of differentiated chondrocytes into the disc will produce proteoglycan and collagen Type I and II under nutrient stress and hypoxia, and meet the cellular demands of the disc. In 2003, a preclinical study was conducted in a canine model by Ganey et al., and it is established that NP disc chondrocyte implantation contributed to ECM regeneration and decelerated disc degeneration.[17] Cell transplantation is an appropriate approach for the regeneration of IVD because of its distinctive organization and structure as the NP is enclosed by the AF and the CEP, which prevents cell migration and permits room for the donor cells to transform. Cell transplantation can increase both the amount of viable cells and accumulation of matrix components. The NP cells have been reported to express Fas ligand which is immune privileged, and thus, some studies considered that the ideal cell candidate for regeneration of IVD may be the disc cells themselves.[18],[19] The use of autologous disc cells is an unconventional approach to repair damaged and chronically inflamed tissue by addressing numerous propagators of degeneration simultaneously. To compare the safety and efficacy of the autologous disc chondrocyte transplantation (ADCT), the first study of ADCT was conducted in a large group of enrolled patients from 2002 to 2006 in a multicenter prospective, randomized, controlled, nonblinded study.[20]

Meisel et al. conducted a study where the patients who received an injection of autologous disc cells showed a reduced amount of fluid content and better pain relief at 24 months when compared with the control group.[21] Nomura et al. (2001) reported that allogeneic rabbits IVD cells slowed down degeneration in a needle puncture model of rabbits IVDD.[22] In a study done by Hohaus et al., the autologous disc cells were implanted in degenerative discs of dogs and they remained viable, produced matrix components such as normal discs, and also retained the disc height. On the basis of the findings, the researchers introduced autologous disc cells in humans following microdiscectomy which is a microdecompression spine surgery, and when compared with the control group at 2 years, the patients showed an increase in the fluid content and pain relief.[23] Gruber et al. conducted studies on the autologous disc cells from sand rats which were expanded in vitro and demonstrated spindle-shaped morphology in the AF and chondrocyte phenotype in NP after transplantation.[24] In 2015, Zhang et al. injected articular chondrocytes into the degenerative disc of rabbits and the study demonstrated the survival of the cells for at least 8 weeks with suppressed inflammation, but the ECM did not resemble the normal NP phenotype.[25] However promising, there are several drawbacks in disk cell transplantation: (1) donor-site morbidity; (2) difficulty expanding cells in vitro while maintaining cell phenotype; (3) scarcity of allograft donor tissue; and (4) issues of immunocompatibility and disease transmission.[26]

The cultured articular chondrocytes are deep-rooted non-disc cell source in the field of regenerative medicine. The extraction of articular chondrocytes is simple as they are from nonweight-bearing parts of the knee and they have the capability to produce NP-like ECM when transplanted in vivo that makes the autologous or allogenic articular chondrocytes a safe and feasible cell source in IVD regeneration.[26] Several in vitro and in vivo studies done using articular chondrocytes injection into degenerated discs of rabbits and porcine models showed promising results.

Stem cell therapy

Stem cell therapies are gaining attention in many neurologic, cardiac, blood diseases and IVDD is no exception. Stem cells are undifferentiated, multipotent cells mainly residing in the bone marrow but also found in many other tissues which are highly accessible and have ability to self-renew, proliferate, and differentiate into multiple mature cell lineages including chondrocytes, and they possess immunomodulatory properties. Stem cells, particularly adult mesenchymal stem cells (MSCs), have been proposed as good alternative and attractive cell choice for regeneration of the IVD as they can be extracted from a variety of adult tissues.[27]

The adult stem cells used in the IVD regeneration include bone marrow-derived MSCs, adipose tissue-derived stem cells, muscle-derived stem cells, hematopoietic stem cells, olfactory membrane stem cells, and synovial stem cells. Adult stem cell types are committed to differentiate into the following lineage of mesenchymal tissues including bone, cartilage, fat, and muscle.[13]

Risbud et al. demonstrated the ability of MSCs differentiating into NP cells when cultured in chondrogenic-culturing conditions; hence, this culture condition can be used as a preconditioning strategy before MSCs implantation into the IVD.[28] Many studies suggested that the regenerative potential of MSCs may be due to the interactions with NP cells and MSCs, and hence, co-culturing system is considered as a powerful tool for investigating the potential of MSC in IVD regeneration. To investigate the compatibility of MSCs in IVD, they are co-cultured with disc cells or tissues in vitro either indirectly or in micromass cultures. A study done by Wei et al. demonstrated the differentiation of rat bone marrow mesenchymal stromal or stem cells (BM-MSCs) into NP-like cells after they were co-cultured with intact IVD tissue in a transwell membrane system where the MSCs were separated from the disc tissue by an insert semipermeable membrane; they demonstrated morphological cell–cell/cell–tissue interactions via the pores through cytoplasmic process.[29] Similar observations were reported in several other studies, which co-cultured MSCs and NP cells under different conditions. Many preclinical studies were conducted using NP cells and MSCs in various animal models [Table 1] and [Figure 3].
Table 1: Preclinical studies conducted till date using various animal models

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Figure 3: Stem cell-based therapy and intervertebral disc regeneration: The figure depicts the steps involved in the stem cell therapy. Stem cells are first isolated and then combined with hydrogels or therapeutic target genes and then injected into the NP of the injured IVD potentially leading to intervertebral disc regeneration[16]

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Sakai et al. studied the transplantation of bone marrow mesenchymal stromal or stem cells (BMSCs) in a rabbit IVDD model and reported that the cells differentiated into NP-like cells with increased proteoglycan content in the disc.[49] In 2015, Cao et al. co-cultured BM-MSCs with NP cells of the rabbits and demonstrated the upregulation in aggrecan, collagen 2, and SOX 9 expression with an anabolic effect on the NP ECM.[50] Elabd et al. injected autologous hypoxia-cultured BM-MSCs into the IVDs of five patients suffering from low back pain and reported that improvement was seen in a small number after 5 years of injection.[51]

Stem cell therapy is associated with many risks and obstacles such as growth of osteophytes in the spinal canal caused by cell leakage and disc infection and tumorigenesis caused by the multipotent nature of stem cells.[52] To mitigate the risk of cell leakage, various biocompatible cell carriers are developed which would provide three-dimensional (3D) structural framework for MSCs to proliferate and changes in physical characteristics once injected so that it would not leak back into the spinal canal. Successful transplantation of MSCs alone or in conjunction with cell carriers in animal-degenerated IVD models showed survival of chondrocyte-like cells, capable of aggrecan production, and increase in disc height.

Stem cell therapy and tissue engineering approaches

In the advanced stages of IVDD, when the cell death and loss of disc tissue are profound, there is a necessity of complex tissue engineering; thus, a multifunctional therapeutic modality has been derived which is to implant an ex vivo engineered tissue block directly into the degenerated IVD.[53] The idea of an additional cell matrix or a scaffold was initiated in order to facilitate the delivery, orientation, differentiation, growth, replication of cells and also in the cellular metabolism, and constant viability. Scaffolds or matrices are artificial 3D frame structures that mimic the ECM, allowing cellular adhesion, migration, and proliferation and therefore playing a cooperative role in tissue regeneration. The materials with desirable viscoelastic properties are often biodegradable; thus, their function may not be sustained in the long term.[4]

Scaffold is a significant factor in the construction and production of engineered disc tissue. Although synthetic scaffolds are those whose mechanical properties match those of the NP, many naturally occurring biopolymers are preferred as they have an advantage of mimicking the extracellular environment regarding mechanical, permeability, and biochemical properties, therefore providing a bioresorbable temporary 3D microenvironment. The ideal scaffold for tissue repair should respond to important criteria that include (a) manufacturing feasibility; (b) mechanical properties to allow short-term function without affecting long-term function of the tissue; (c) low toxicity of degradation products, in terms of both local tissue response and systemic response; and (d) drug delivery compatibility.[7] The naturally occurring biopolymers can be used alone or in combination as hydrogel scaffolds for both in vitro and in vivo MSC preparation and treatment. A study done by Betram et al., 2005 compared the intradiscal injection of cells suspended in medium and in an injectable fibrin matrix, where rapid loss of cells was observed when injected with medium but the fibrin matrix maintained the injected cells in the NP as fibrin matrix could polymerize after the injection.[54]

Hydrogel scaffolds have been frequently used in tissue engineering, with the objective of maintaining the newly deposited proteoglycan to facilitate the establishment of hydrostatic pressure in the NP. Even though numerous studies have been reported and acknowledged on the efficiency and efficacy of various hydrogel-based scaffolds which are either constructed from natural hydrophilic biomolecules or synthetic polymers, one of the most frequently accepted hydrogel scaffolds for the culturing of NP cells is alginate due to its ease of management, biodegradability, and inert bioactivities.[55],[56]

Current research in the field of bioengineering in NP cells has attempted to use injectable scaffolds as carriers to deliver cells with the aim of salvaging disc degeneration or as fillings for NP replacement using a minimally invasive approach.[57] Biomaterials such as atelocollagen form a fibrous meshwork as they can self-crosslink. Hyaluronan and chitosan when adapted and modified with cross-linkable moieties are capable of chain polymerization through photochemical reactions.[58] These materials, as injectable media, may deliver cells of interest by providing a transient framework that prevents leakage of implants and allows the growth of the ECM deposited by the introduced cells. The preclinical studies using various bio-scaffolds in tissue engineering are summarized in [Table 2].
Table 2: Preclinical studies on tissue engineering using bio-scaffolds

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The literature review has given us an understanding in regard to the varied cell types and scaffolds used and outcomes in the area of IVDD. Based on the outcomes reported till date, it is only indicating that the effectiveness of cell therapy in tissue engineering could be a putative mode of treatment for addressing the IVDD effectively in the near future [Figure 4].
Figure 4: Classification of the various biomaterials used in the tissue engineering strategies for the treatment of intervertebral disc degeneration

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Clinical studies

The transplantation of MSCs for the treatment of IVDD in human clinical trials has shown encouraging outcomes.[27] As of November 2016, a total of eight published and 12 unpublished clinical trials assessing cellular transplantation for IVD regeneration were identified. Autologous and allogeneic cells have been used in clinical trials, but xenogeneic cells have only been used in animal studies. The information presented in [Table 3] has been collected from the clinical trials registry database.[80]
Table 3: Ongoing clinical studies on intervertebral discs regeneration using cell therapy

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EuroDISC trials

The groups of scientists representing a scientific consortium known as EuroDISC have published their finding and insights on IVDD and its treatment strategies. Scientists employed hematopoietic precursor stem cells (HSCs), MSCs and chondrocytes collected from autologous source and transplanted into the patients to assess the efficiency of HSCs, MSCs, and chondrocytes in the patients enrolled for the clinical trials. The study done by Haufe and Mork reported that the 10 patients who underwent transplantation of autologous HSCs into discs did neither yield any encouraging results nor reduced the low back pain; hence, 80% of the patients opted for surgery.[81] The study conducted by Meisel et al. on 28 patients who opted for undergoing level one microdisc surgery, autologous chondrocytes were isolated and cultured in in vitro and transplanted into the patients 3 months after the surgery and monitored their progress for the next 2 years, and it was found that the low back pain reduced gradually and the magnetic resonance imaging (MRI) T2 signal in NP cells also improved in treated and adjacent discs.[82] Yoshikawa et al. administered autologous MSCs into the collagen sponge of two IVDD patients and it was noticed that their low back pain and radicular symptoms ameliorated within 2 years.[83] In another study done by Orozco et al., they reported that 90% of participants among the 10 patients enrolled in the study who were suffering from chronic low back pain and degenerative disc disease recovered significantly after administration of autologous MSCs into their intradiscal space.[84]

[Table 4] shows the published clinical trials targeting the regeneration of intervertebral disc.
Table 4: Completed clinical studies on intervertebral discs regeneration using cell therapy

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The results from the 12 ongoing clinical trials being conducted in the USA, European countries (Germany, Spain, Belgium, and Austria), and Korea are yet to be published in the online clinical trials database.

[Table 3] shows the registered clinical trials retrieved from the database available at clinical trials.gov on the treatment of IVDD with low back pain and the use of cell therapy.


  Conclusion Top


Cell therapy is an attractive and appealing approach to regenerate the IVD, due to the slow and progressive nature of the degeneration that includes an increase in catabolic activity, resulting in the decreased matrix synthesis and cell senescence. The current knowledge specifies that cell therapy is safe although long-term results are unknown. Although much of the published animal data on the regenerative potential of injected chondrocyte or disc cells are promising for the regeneration of early IVDD, there are many questions that need to be answered regarding the timing of the treatment, optimal cell source, cell pretreatment, and cell carriers in humans. With the increasing number of clinical trials, cell therapy for IVD regeneration could bridge the disparity between aggressive surgical interventions and symptomatic care in some patients with IVD disease. A critical element for achieving natural tissue regeneration is to comprehensively understand the biological events required for the process of regeneration for each tissue and understand the IVD niche which is the major obstacle for regeneration of the IVD using cell therapy.

There are certain questions that need be answered or considered:

  1. Cell therapy mainly involves the implantation of one type of cells directly into the disc. Can the cells be implanted directly into the disc and differentiate into the desired populations required to regenerate a stable NP and repair the annulus fibrous layer and endplate?
  2. According to a study done by Brinjikji et al., 2015, many patients with severe disc degeneration are asymptomatic and not aware of having any spinal problems.[88] Therefore, the question is whether pain should be the clinical target rather than IVDD itself?
  3. IVD niche is also an obstacle for successful regeneration using cell therapy. The major challenge is the survival and function of the injected cells in the IVD disc.


Hence, more clinical trials and better understanding should be our key for finding the best and amicable way for treating IVDD or at least ameliorate the IVDD in the best possible way for reconstruction and regeneration of the disc.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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